CN101686975A - Antitumour combinations containing a vegf inhibiting agent and irinotecan - Google Patents
Antitumour combinations containing a vegf inhibiting agent and irinotecan Download PDFInfo
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- CN101686975A CN101686975A CN200880023537A CN200880023537A CN101686975A CN 101686975 A CN101686975 A CN 101686975A CN 200880023537 A CN200880023537 A CN 200880023537A CN 200880023537 A CN200880023537 A CN 200880023537A CN 101686975 A CN101686975 A CN 101686975A
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- irinotecan
- vegf
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
Antitumour combinations of VEGF inhibitors with Irinotecan of therapeutic use in the treatment of neoplastic diseases.
Description
The present invention relates to the combination that can be used for treating tumor disease of the chemotoxic agents of VEGF inhibitor and topoisomerase enzyme inhibitor class.
The VEGF inhibitor is the inhibitor of vascular endothelial cell growth factor, is the biological product that are selected from soluble recepter, antisense, RNA aptamers and antibody in most applications.The inhibitor that is used for the treatment of the topoisomerase of known cancer disease is selected from camptothecin, and it comprises CPT 11, topotecan and pyridobenzoindole.Combination of the present invention is directed to treatment colon cancer or gastric cancer especially.
The description and the preparation that are preferred for VEGF inhibitor of the present invention (it is VEGF Trap chimeric protein) are described among the patent application WO 00/75319.The acquisition mode that has many chimeric proteins.
The acquisition mode of corresponding VEGF Trap is be described in Figure 24 (sequence) the sort of.Being used for VEGF Trap of the present invention is fusion rotein, it comprises the VEGFR1 signal sequence that merges with the Ig D2 domain of VEGFR1 receptor, the Ig D2 domain self of VEGFR1 receptor then merges with the Ig D3 domain of VEGFR2 receptor, the Ig D3 domain of VEGFR2 receptor and merge with the Fc domain of IgG1, it is known as VEGFR1R2-Fc Δ C1 or Flt1D2Flk1D3Fc Δ C1 again.
Usually, be used for the specific factors that human VEGF Trap dosage depends on individuality to be treated, when subcutaneous or intravenous route carried out administration, this dosage was generally 1～10 mg/kg.
In the inhibitor of topoisomerase, irinotecan (nonproprietary name is also referred to as CPT-11) is preferably used.
According to dosage regimen, irinotecan is usually with 100mg/m
2～500mg/m
2Dosage use by intravenous route.For example, be 150mg/m for weekly scheme
2Dosage, be 200～400mg/m for the scheme in per three weeks
2Dosage.
Be published in the H Hurwitz in " The New England Journal of Medicine ", L Fehrenbacher, W Novotny, T Cartwright, J Hainsworth, W Heim, J Berlin, A Baron, S Griffing, E Holmgren, N Ferrara, G Fyfe, B Rogers, R Ross, the paper of F Kabbinavar has been described a kind of clinical trial, its proof is used bevacizumab (bevacizumab) and irinotecan, during the combination of 5FU and formyl tetrahydrofolic acid, compare, obtained better survival rate with the like combinations that does not contain bevacizumab.In this clinical trial, do not prove that the improvement of survival rate comes from the combination of irinotecan and bevacizumab, it may come from the combination of 5FU or formyl tetrahydrofolic acid and bevacizumab, perhaps can come from the combination of four kinds of compositions.Now, owing to known that various anticarcinogens follow its therapeutic effect can cause toxic side effects, therefore, seeming wise is the existence that limits them as far as possible, particularly can at least aly still can obtain identical effect when not existing at them.In addition, this piece paper does not provide any cooperative effect on section's bit (Corbett) meaning, the i.e. effect that all can't obtain when using the various element of combination separately with its maximum tolerated dose.
VEGF Trap is a kind of soluble recepter, and it is to produce by following fusion: the 2nd Ig domain of EGFR-1 and the 3rd Ig domain of EGFR-2 merge (fusion), the 3rd Ig domain of this EGFR-2 subsequently again with the Fc partial fusion of people's IgG1.As the VEGFR-1 receptor, A Baixipu (aflibercept) (VEGF Trap) has very high affinity to VEGF-A, and its Kd is 0.5 skin M.VEGF Trap causes forming complex with the combining of high-affinity of VEGF-A, and this complex stops VEGF to be attached on the cell surface and activates its receptor on cell surface.
Compare with A Wasiting (Avastin) (or bevacizumab), VEGF Trap is a kind of soluble recepter, and A Wasiting then is the antibody at VEGF-A.Compare with A Wasiting, VEGFTrap has the much higher affinity to VEGF-A, and have different selectional features,, promptly be connected to PlGF (placental growth factor) and be connected to VEGF-B because VEGF Trap also is connected with other part of VEGFR1-2 receptor.On the other hand, VEGF Trap has than the remarkable low molecular weight of A Wasiting (A Baixipu is 115kDa, and A Wasiting is 160kDa), and it more helps infiltrating in the solid tumor.
Have been found that now and this also is a theme of the present invention that when administration was carried out in they and at least a therapeutant combination that is used for having of the anticancer therapy mechanism of action different with the VEGF inhibitor, the efficient of VEGF inhibitor can be improved significantly.
And, because product activity depends on employed dosage, so can use higher dosage and improve activity by the appearance (making up) that reduces the toxicity phenomenon or delay them by combination and VEGF inhibitor or they analog with the therapeutic active substance (for example G-CSF or GM-CSF or some interleukin) of other hemopoietic type somatomedin.
More particularly, the present invention relates to the combination of VEGF Trap and irinotecan.
The efficient of the improvement of combination of the present invention can obtain proof by determining the treatment synergism.
If it is superior to a kind of and another kind of of the described component used with optimal dose in treatment, then combination demonstrates the treatment synergism.
In order to prove the efficient of combination, can need the maximum tolerated dose of the isolating various components in maximum tolerated dose that will make up and the research of being considered to compare.This efficient can be for example by the log of the cell of being killed
10(log
10Des cellules tu é es) carry out quantitatively, it is to determine according to following formula:
The log of cell is killed
10=T-C (my god)/3.32 * T
d
Wherein, T-C represents the delay of cell growth, and it is that to have reached predetermined value (for example 1g) for the tumor through the tumor of the group (T) of treatment and matched group (C) be the average time of unit with the sky, T
dRepresent gross tumor volume in control animal double needed with the sky be unit time [people such as T.H.Corbett, Cancer,
40, 2660.2680 (1977); People such as F.M.Schabel, Cancer Drug Development, Part B, Methods in Cancer Research,
17, 3-51, New York, Academic Press Inc. (1979)].The log of cell if be killed
10More than or equal to 0.7, then product is considered to activated.The log of cell if be killed
10Greater than 2.8, then product is considered to very activated.
The combination of using with its oneself maximum tolerated dose (all existing with the dosage that is usually less than or equal its maximum tolerated dose at every kind of component described in this combination) is at the log of cell that is killed
10Log greater than best component cell killing when it is individually dosed
10The time, then will demonstrate treatment cooperative effect, particularly exceedance when being at least 1 log cell killing.
Described combination can be tested definite to the efficient of solid tumor in the following manner:
At the 0th day, with animal (being generally mice) both sides subcutaneous implantation 30～60mgHCT116 people tumor fragment (Brattain, the MG. that experimentizes, Fine, W.D., Khaled, F.M., Thompson, J. and Brattain, D.E., Heterogeneity of malignant cells from ahuman colonic carcinoma.Cancer Res., 1981,41,1751-1756).Before carrying out various treatments and contrast, be at random with the animal of carrying tumor.In the situation of treatment tumor of the present invention, make the size of tumor development to 48～294mg, this can obtain the intermediate value tumor between every group of 129～162mg.Experience is 17.1～22.7g with the weight of the animal of the treatment of VEGF Trap separately, and experience is 17.5～22.3g with the weight of the animal of irinotecan separately, and the weight of those animals that acceptance is made up is 17.5～23.6g.The animal of carrying tumor has also carried out only utilizing the identical treatment of excipient, can isolate the toxic action of excipient from the actual effect of chemotherapy to tumor.The 12nd day beginning of this chemotherapy after tumor is implanted.With injection irinotecan (according to injecting twice every day, they are undertaken by intravenous route) simultaneously, carry out VEGF Trap injection by subcutaneous route.These injections are that carry out the 12nd, 15 and 18 day behind implantation tumour.Weekly the animal of each group is weighed 3～4 times, alleviate, then weekly these groups are weighed at least once up to off-test up to reaching maximum weight.
Weekly tumor is measured 2 or 3 times, reached about 2g, perhaps up to animal dead (if before tumor reaches 2g, taking place dead) up to tumor.When putting to death, animal is carried out dissection and analysis.
Parameter according to various records is determined anti-tumor activity.
As an example, the form of back provides the result that combination was obtained who utilizes VEGF Trap and irinotecan (using with their optimal doses).
The invention still further relates to the test kit of pharmaceutical composition, it contains the product that uses in combination according to the present invention.
The product that constitutes combination can be by simultaneously, separately or ground administration successively in time so that obtain the maximal efficiency of combination; Each administration can have the different persistent period, from the quick and complete continuous infusion that is administered into.
For purpose of the present invention, as its result, combination is not restricted to by these component physical combination are obtained those, and is not limited only to allow separate administration (its can be simultaneously or successively in time) those.
Compositions of the present invention preferably can be by the compositions of parenteral route administration.
The compositions that is used for parenteral is acceptable sterile solution or suspension on the medicine normally, its randomly preparation provisionally in use.In order to prepare non-aqueous solution or suspension, can use for example olive oil, Oleum sesami or liquid paraffin or injectable organic ester ethyl oleate for example of natural vegetable oil.Aqueous sterile solution can be made of the solution of product in water.Described aqueous solution can suitably be regulated and be obtained to be suitable for intravenous administration aspect the isotonicity sodium chloride or the glucose of sufficient amount (for example by) at pH.Sterilization can be undertaken by heating or any measure that other does not damage composition.Described combination can also be the liposome form, perhaps with the form of carrier (for example cyclodextrin or Polyethylene Glycol) combination.
In combination of the present invention, using of its component can be simultaneously, that separate or successively in time, particularly advantageously, the amount of VEGF Trap derivant accounts for the 10 weight %～80 weight % of combination, and this content can change according to the character of the efficient of the character of related substances, expectation and cancer to be treated.
Combination of the present invention can be used for the treatment of colon cancer and/or gastric cancer especially.Especially, they can have the advantage that the much lower dosage of dosage with than their independent use the time uses these components.
The following examples have been described according to combination of the present invention.
Embodiment
Prepare to be used for the 1cm of subcutaneous administration according to common technology
3Ampulla, it contains 25mgVEGF Trap, described VEGF Trap is diluted in the buffer of 5mM phosphate, 5mM sodium citrate, 100mM sodium chloride, polysorbate20 and 20% sucrose.The administration volume of every mice is 0.1ml.Behind implantation tumour the 12nd, 15 and 18 day, administration every day VEGFTrap once.
According to common technology, prepare to be used for every mice 0.3ml intravenous administration by the commercial solution (with the aqueous solution dilution of 5% dextrose) of 20mg/ml irinotecan.
After suitable dilution, these solution of administration simultaneously.
Behind implantation tumour the 12nd, 15 and 18 day repeated to utilize for twice the treatment of irinotecan in one day, was spaced apart 4 hours.
Result of the test invests in the table of back.
Double time=3.2 of tumor day.
Employed abbreviation: (T-C) delay of tumor growth, the log value of lck=cell killing.
For independent irinotecan, 52.4,32.5 and the dosage of 20.2mg/kg/ injection, observed toxicity, because death is arranged, then observe for two other lower dosage and to surpass 20% weight saving at 52.4 dosage.Therefore, the maximum tolerated dose for irinotecan is 12.5mg/kg/ injection (the injection accumulated dose is 75.0mg/kg).12.5mg/kg/ it is activated that the dosage of injection is found to be, its lck is 1.8.
For VEGF Trap, this product is fine tolerance under all dosage of being tested, and finds it is activated, and its lck when 40mg/kg/ administration and 25mg/kg/ administration is 1.7.Than low dosage 10mg/kg/ administration also is activated, and its lck is 1.3.Dosage 2.5mg/kg/ administration is a non-activity.
Combination for the irinotecan of 32.5mg/kg/ injection, regardless of VEGF Trap be, find that this combination is virose, have and approach toxic 18% weight saving.Irinotecan and 40mg/kg VEGF Trap than low dosage 20.2mg/kg/ injection are considered to maximum tolerated dose.The lck of this dosage is 3.0, and be judged as has activity very much.Utilization has been found identical activity level, (lck is respectively 2.9,3.0 and 2.9) than the VEGF Trap of low dosage (for example 25,10,2.5mg/kg/ administration).
With the irinotecan of the 12.5mg/kg/ injection of the VEGF Trap of 40mg/kg/ administration combination be activated, its lck is 2.7.With 25 and 10mg/kg VEGF Trap kept this anti-tumor activity (lck is respectively 2.9 and 2.7).With the activity of the combination of 2.5mg/kg/ administration VEGF Trap be 2.0lck
Generally speaking, under the maximum tolerated dose of this combination, the activity of the combination of VEGF Trap and irinotecan has shown cooperative effect, it is 3.0 that its log cell kills (log cell kill), compare (it has 1.8 and 1.7 log cell and kills (respectively for the irinotecan of 12.5mg/kg/ injection and the VEGF Trap of 40mg/kg/ administration)) with the activity of every kind of chemical compound of independent use, it is equivalent to exceed 1 log cell and kills.A plurality of dosage levels below the maximum tolerated dose of combination have all kept anti-tumor activity.
Claims (5)
1. comprise the combination of VEGF inhibitor and irinotecan, it has the therapeutic use of treatment tumor disease.
2. according to the combination of claim 1, it comprises VEGF Trap inhibitor and irinotecan.
3. according to claim 1 and 2 each combinations, it is characterized in that it contains the VEGF Trap of 10 weight %～80 weight %.
In tumor disease therapeutic as the product that comprises VEGF inhibitor and irinotecan of combination preparation, this combination preparation in anticancer therapy simultaneously, separately or in time successively use.
5. do not comprise the combination that comprises VEGF Trap inhibitor and irinotecan of any other chemical toxicity derivant, it has the treatment cooperative effect in the treatment of tumor disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610141168.3A CN105833244A (en) | 2007-07-05 | 2008-07-02 | Antitumor combinations containing a VEGF inhibiting agent and Irinotecan |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0704868A FR2918279B1 (en) | 2007-07-05 | 2007-07-05 | ANTITUMOR COMBINATIONS CONTAINING A VEGF INHIBITOR AGENT AND IRINOTECAN |
| FR0704868 | 2007-07-05 | ||
| PCT/FR2008/000943 WO2009024667A2 (en) | 2007-07-05 | 2008-07-02 | Antitumour combinations containing a vegf inhibiting agent and irinotecan |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610141168.3A Division CN105833244A (en) | 2007-07-05 | 2008-07-02 | Antitumor combinations containing a VEGF inhibiting agent and Irinotecan |
| CN201310556556.4A Division CN103623392A (en) | 2007-07-05 | 2008-07-02 | Antitumour combinations containing a vegf inhibiting agent and irinotecan |
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| Publication Number | Publication Date |
|---|---|
| CN101686975A true CN101686975A (en) | 2010-03-31 |
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Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610141168.3A Pending CN105833244A (en) | 2007-07-05 | 2008-07-02 | Antitumor combinations containing a VEGF inhibiting agent and Irinotecan |
| CN200880023537A Pending CN101686975A (en) | 2007-07-05 | 2008-07-02 | Antitumour combinations containing a vegf inhibiting agent and irinotecan |
| CN201310556556.4A Pending CN103623392A (en) | 2007-07-05 | 2008-07-02 | Antitumour combinations containing a vegf inhibiting agent and irinotecan |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610141168.3A Pending CN105833244A (en) | 2007-07-05 | 2008-07-02 | Antitumor combinations containing a VEGF inhibiting agent and Irinotecan |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201310556556.4A Pending CN103623392A (en) | 2007-07-05 | 2008-07-02 | Antitumour combinations containing a vegf inhibiting agent and irinotecan |
Country Status (24)
| Country | Link |
|---|---|
| US (3) | US20100160233A1 (en) |
| EP (1) | EP2173349B1 (en) |
| JP (4) | JP2010532335A (en) |
| KR (4) | KR20150048910A (en) |
| CN (3) | CN105833244A (en) |
| AR (1) | AR067420A1 (en) |
| AT (1) | ATE500829T1 (en) |
| AU (1) | AU2008290442B2 (en) |
| BR (1) | BRPI0812835B8 (en) |
| CA (1) | CA2693152C (en) |
| CY (1) | CY1111675T1 (en) |
| DE (1) | DE602008005457D1 (en) |
| DK (1) | DK2173349T3 (en) |
| ES (1) | ES2362637T3 (en) |
| FR (1) | FR2918279B1 (en) |
| HR (1) | HRP20110432T1 (en) |
| IL (2) | IL203132A (en) |
| MX (1) | MX2009013950A (en) |
| PL (1) | PL2173349T3 (en) |
| PT (1) | PT2173349E (en) |
| RS (1) | RS51777B (en) |
| RU (1) | RU2471483C2 (en) |
| SI (1) | SI2173349T1 (en) |
| WO (1) | WO2009024667A2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA05002444A (en) | 2002-09-06 | 2005-09-30 | Insert Therapeutics Inc | Cyclodextrin-based polymers for delivering the therapeutic agents covalently bound thereto. |
| US20080176958A1 (en) | 2007-01-24 | 2008-07-24 | Insert Therapeutics, Inc. | Cyclodextrin-based polymers for therapeutics delivery |
| US20110223241A1 (en) * | 2008-10-16 | 2011-09-15 | Celator Pharmaceuticals, Inc. | Combination methods and compositions |
| ES2354922B1 (en) | 2009-09-02 | 2012-02-07 | Fundacion Institut De Recerca De L'hospital Universitari Vall D'hebron | MARKERS FOR THE SELECTION OF PERSONALIZED THERAPIES FOR THE TREATMENT OF THE C�? NCER. |
| US20130029909A1 (en) * | 2009-09-15 | 2013-01-31 | John Ryan | Treatment of cancer |
| WO2012097019A1 (en) | 2011-01-13 | 2012-07-19 | Regeneron Pharmaceuticals, Inc. | Use of a vegf antagonist to treat angiogenic eye disorders |
| JO3283B1 (en) * | 2011-04-26 | 2018-09-16 | Sanofi Sa | Composition comprising aflibercept, folinic acid, 5-fluorouracil (5-fu) and irinocetan (folfiri) |
| US20140094432A1 (en) | 2012-10-02 | 2014-04-03 | Cerulean Pharma Inc. | Methods and systems for polymer precipitation and generation of particles |
| TR201909951T4 (en) | 2014-07-18 | 2019-07-22 | Sanofi Sa | A method for predicting the outcome of aflibercept treatment of a patient suspected of having cancer. |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0011407B8 (en) * | 1999-06-08 | 2021-05-25 | Regeneron Pharma | chimeric nucleic acid molecule, fusion polypeptide, expression vector, host vector system, and methods of producing a fusion polypeptide |
| CN1276923C (en) * | 2002-03-01 | 2006-09-27 | 法玛西雅意大利公司 | Crystalline polymorphic form of irinotecan hydrochloride |
| AR046510A1 (en) * | 2003-07-25 | 2005-12-14 | Regeneron Pharma | COMPOSITION OF A VEGF ANTAGONIST AND AN ANTI-PROLIFERATIVE AGENT |
| WO2005016369A1 (en) * | 2003-08-06 | 2005-02-24 | Regeneron Pharmaceuticals, Inc. | Use of a vegf antagonist in combination with radiation therapy |
| JP2008503481A (en) * | 2004-06-18 | 2008-02-07 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | Methods of administration and use of VEGF inhibitors for the treatment of malignant pleural effusion |
| FR2878749B1 (en) * | 2004-12-03 | 2007-12-21 | Aventis Pharma Sa | ANTITUMOR COMBINATIONS CONTAINING IN VEGT INHIBITOR AGENT AND 5FU OR ONE OF ITS DERIVATIVES |
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2019
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